Verselis Vytas K, Bukauskas Feliksas F
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Curr Drug Targets. 2002 Dec;3(6):483-99. doi: 10.2174/1389450023347272.
Important roles for connexins have emerged from studies linking connexin mutations to human disease. Use of connexins tagged with GFP have provided a clearer picture of the mechanisms that govern connexin channel function and it is now evident that functional forms of connexin channel include cell-cell channels and unapposed hemichannels. Clustering appears to be a requirement for opening of cell-cell channels and suggests that dynamic changes occur in plaques (clusters) as they form and grow that are critical for channel function. In particular, recruitment or generation of 'silent' channels has gained support as a mechanism by which coupling can be dynamically regulated within formed plaques. Two distinct voltage sensitive gating mechanisms appear to be built-into each hemichannel, one putatively located at the cytoplasmic entrance and the other at the extracellular end, each differing in sensitivity, kinetics and degree of channel/hemichannel closure. The extracellular gate may also be that which opens unapposed hemichannels in the plasma membrane and be the final target of many known chemical agents that act as uncouplers of cell-cell communication. An understanding of the structural requirements for regulation via gating and clustering represents an important preclinical step in the design of therapeutic agents to treat disorders arising from connexin channel and hemichannel dysfunction.
连接蛋白的重要作用已在将连接蛋白突变与人类疾病联系起来的研究中显现出来。使用标记有绿色荧光蛋白（GFP）的连接蛋白，已更清楚地了解了控制连接蛋白通道功能的机制，现在很明显，连接蛋白通道的功能形式包括细胞间通道和未对接的半通道。聚集似乎是细胞间通道开放的必要条件，这表明在斑块（聚集体）形成和生长过程中会发生动态变化，而这些变化对通道功能至关重要。特别是，“沉默”通道的募集或产生作为一种机制已得到支持，通过该机制可以在已形成的斑块内动态调节耦合。似乎每个半通道都内置了两种不同的电压敏感门控机制，一种可能位于细胞质入口处，另一种位于细胞外端，每种机制在敏感性、动力学和通道/半通道关闭程度方面都有所不同。细胞外门控也可能是打开质膜中未对接半通道的门控，并且是许多已知化学试剂的最终作用靶点，这些化学试剂充当细胞间通讯的解偶联剂。了解通过门控和聚集进行调节的结构要求是设计治疗因连接蛋白通道和半通道功能障碍引起的疾病的治疗药物的重要临床前步骤。
